Analgesic potentiation

ABSTRACT

A method of producing analgesia by administering m-benzoylhydratropic acid or a salt thereof together with acetaminophen and compositions therefor.

This invention is directed to improved methods and compositions for producing analgesia.

BACKGROUND OF THE INVENTION

One of the long existing primary goals of medicine is the relief of pain. Relief is sought most generally by the administration of analgesic drugs which produce a state of decreased awareness of the sensation and increase of the pain threshold.

Almost all potent analgesics evoke reactions other than the relief of pain. Some of the reactions are gastrointestinal disturbances, nausea, constipation and vomiting. Among the more serious of the side reactions and one frequently found in analgesic drugs is respiratory depression. Thus, in the use of analgesics in man, considerations other than the primary effect (analgesia), must be made and drugs for pain relief are sought which have maximum analgesic effect accompanied by minimum side reactions. It is difficult to satisfy these requirements with a single chemical entity since generally a potent analgesic has accompanying serious side reactions while a drug with little or no side effects are generally less effective as an analgesic.

Thus, there is a continuing search for a combination of two or more drugs whereby the total quantity of drug can be reduced and which can be employed in such proportions as to produce maximum analgesic effect with little or no side effects. When one or both of the components of a combination is known to possess pain relieving properties but these properties are increased many fold, the net effect of the combination is commonly referred to as "potentiation."

Acetaminophen (p-acetaminophenol) is recognized as an analgesic agent with useful antinociceptive properties. However, in certain instances, high doses must be employed to effectively reduce pain. m-Benzoylhydratropic acid is known by the generic name of "ketoprofen" for use as an anti-inflammatory agent; it also has some analgesic properties. However, the effect of the combination of these two drugs on the analgesic properties was not known prior to our work.

STATEMENT OF THE INVENTION

The present invention concerns an improved method of producing analgesia made possible by the discovery that a potentiation of analgesic or antinociceptive properties of m-benzoylhydratropic acid or its salt is produced by administration with acetaminophen in specific proportions. The efficacy of the combination in the suppression of pain is unexpectedly much greater than that which would result from simply the additive effective of the components.

DESCRIPTION OF THE INVENTION

The novel and unexpected superior analgesic properties may be achieved by the simultaneous or sequential oral administration of (1) acetaminophen and (2) a m-benzoylhydratropic acid compound, said compound being m-benzoylhydratropic acid (ketoprofen) represented by the formula ##STR1## or a therapeutically acceptable salt thereof. The therapeutically acceptable salts are those obtained from appropriate organic or inorganic bases. Preferred salts include these of sodium, potassium and the like.

The efficacy of the novel combination in producing antinociceptive properties is particularly seen in acetylcholine bromide abdominal constriction assay of Collier et al [(Brit. J. Pharmacol. Chemotherap. 32, 295-310 (1968)] sometimes referred to as the "mice writhing test." In the test, mice are dosed with test drug combinations and thereafter injected interperitoneally with acetylcholine bromide and the abdominal constriction responses or block of abdominal constriction responses are observed and compared with control operations.

More specifically, in an operation carried out substantially as described by Collier and co-workers, non-fasted albino mice weighing 18-24 grams were dosed with combinations of one test drug in selected fixed doses together with a second test drug at variable doses for each fixed dose. These were compared with animals dosed with (a) the first test drug at the same doses used in combination but employing saline instead of the second drug, (b) the second test drug at the doses used in combination but employing saline instead of the first drug, and (c) a saline control containing no drug. Each of the drugs, when separately employed, were found to be inactive in the acetylcholine bromide abdominal constriction test at the test dose level.

In carrying out the tests, the test compositions and the control compositions both with and without drugs were administered orally to the test mice. After about 30 minutes the mice were injected intraperitoneally with acetylcholine bromide and the abdominal constriction responses compared (corrected for saline responses as necessary). The results are expressed as percent block.

When the percent block of abdominal constriction observed with the fixed dose was 5 percent or more, the percent block observed with each of the combination dosage levels was corrected with respect to the percent block observed with a fixed dose drug using Abbott's formula for natural mortality.

Likewise, when the response to acetylcholine bromide in the saline control group was 95 percent or less, the response observed with each of the variable dosage levels used in the ED₅₀ determination was similarly corrected using Abbott's formula for natural mortality. ED₅₀ and 95 percent confidence limits were calculated according to Finney's probit analysis procedure. (Finney, D. J., 1964, Probit Analysis, Second Edition, University Press, Cambridge.) All ED₅₀ for a given comparison were calculated using a common slope following a test parallelism. All paired dose response curves were found to be parallel.

Employing the above-described procedures, potentiation of the analgesic properties of a m-benzoylhydratropic acid compound (hereinafter sometimes referred to as "ketoprofen compound") by acetaminophen may be demonstrated. The property is illustrated employing ketoprofen (acid form) but it is to be understood that it is not limited thereto.

Non-fasted male albino mice weighing 18-24 grams were dosed initially per os (p.o.) with ketoprofen at various doses and with saline as seen in Tables IA and IB, and fifteen minutes later with acetaminophen at 25 mg/kg or at 50 mg/kg. All dose levels of test drug and saline controls were given as and are expressed as per os. Twenty mice were employed for each dosage level. As controls, a similar number of mice were dosed with (a) acetaminophen (25 mg/kg) plus saline (10 ml/kg) or acetaminophen (50 mg/kg) plus saline (10 ml/kg) and (b) double dose of saline (10 ml/kg). Ketoprofen was administered as a solution in aqueous sodium hydroxide. Acetaminophen was administered as an aqueous suspension. (Where "mg/kg" or "ml/kg" is employed, "kg" is in reference to body weight.)

Twenty minutes after administration of ketoprofen (and fifteen minutes after administration of acetaminophen), the mice were injected intraperitoneally (i.p.) with 5.5 mg/kg of acetylcholine bromide and observed for the presence or absence of the abdominal constriction response. ED₅₀ values were determined from the observed values applying where pertinent corrections previously discussed. The results are seen in Tables IA and IB.

(Where "mg/kg" or "ml/kg" is employed, "kg" is in reference to body weight.)

                                      TABLE I-A                                    __________________________________________________________________________              KETOPROFEN                                                                              OBSERVATION         KETOPROFEN                                        DOSE     Number Responding                                                                        PERCENT   (95% CL***)                              TREATMENT                                                                               (mg/kg)  Number Injected                                                                          BLOCK  ED.sub.50                                                                         (mg/kg)                                  __________________________________________________________________________     Ketoprofen plus                                                                         5.0       0/20     100                                                                               (100)*                                                                             0.47                                                                               (0.31-0.71)                             Saline (10 ml/kg)                                                                       1.0      3/20      85 (83)*                                                    0.5      10/20     50 (44)*                                                    0.25     13/20     35 (28)*                                                    0.10     17/20     15 (6)*                                            Ketoprofen plus                                                                         1.0      3/20      85 (83)**                                                                             0.31                                                                               ( .21-0.47)                             Acetaminophen,                                                                          0.5      5/20      75 (72)**                                          25 mg/kg 0.25     12/20     40 (33)**                                                   0.10     15/20     25 (17)** -Acetaminophen,                                                             --  18/20 10 (0)                            25 mg/kg plus                                                                  Saline, 10 ml/kg                                                               Saline, 10 ml/kg                                                                        --       18/20     10 (0)                                             plus Saline,                                                                   10 ml/kg                                                                       __________________________________________________________________________      *Percent block corrected for saline response.                                  **Percent block corrected for acetaminophen plus saline response.              ***Confidence limits                                                     

                                      TABLE I-B                                    __________________________________________________________________________              KETOPROFEN                                                                              OBSERVATION          KETOPROFEN                                       DOSE     Number Responding                                                                        PERCENT    (95% CL***)                             TREATMENT                                                                               (mg/kg)  Number Injected                                                                          BLOCK  ED.sub.50                                                                          (mg/kg)                                 __________________________________________________________________________     Ketoprofen plus                                                                         1.0       1/20     95 (94)*                                                                              0.46                                                                               (0.29-0.71)                             Saline (10 ml/kg)                                                                       0.75     5/20      75 (71)*                                                    0.50     11/20     45 (35)*                                                    0.25     15/20     25 (12)*                                           Ketoprofen plus                                                                         1.0      0/20      100                                                                               (100)**                                                                            0.19                                                                               (0.13-0.28)                             Acetaminophen,                                                                          0.5      2/20      90 (86)**                                          50 mg/kg 0.25     6/20      70 (57)**                                                   0.10     11/20     45 (21)**                                                   0.05     12/20     40 (14)**                                          Acetaminophen,                                                                          --       14/20     30 (18)                                            50 mg/kg plus                                                                  Saline, 10 ml/kg                                                               Saline, 10 ml/kg                                                                        --       17/20     15  --                                             plus Saline,                                                                   10 ml/kg                                                                       __________________________________________________________________________      *% block corrected for saline response                                         **% block corrected for acetaminophen saline response                          ***Confidence limits                                                     

The foregoing results illustrate the potentiation of the analgesic or antinociceptive properties of a ketoprofen compound by acetaminophen.

The process of the present invention, namely, a method of producing analgesia, comprises orally administering to subjects, i.e., human and other warm-blooded animals suffering from pain, a ketoprofen compound and acetaminophen in amounts sufficient to have an antinociceptive effect. The agents may be administered simultaneously or sequentially and either agent may be administered first. By the administration of the amounts of the agents as hereinafter set forth, an antinociceptive interaction between the drugs is achieved which is wholly unexpected from the known properties of the components. The active agents may be administered with or without carrier. One method of administration is by use of compositions in unit dosage form which provides a convenient simultaneous administration method.

From the foregoing test results on mice and the known dosage ranges of the components as applied to man when employed alone, it is determined that generally from about 0.2 to 0.83 mg/kg of ketoprofen compound may be employed together with from about 2.8 to 7.5 mg/kg of acetaminophen; preferably from about 0.33 to 0.67 of ketoprofen compound with from about 3.3 to 7.1 mg/kg of acetaminophen. These amounts when expressed as doses suitable for man are in the range of from about 12 to 50 milligrams of ketoprofen compound and from about 170 to 450 milligrams of acetaminophen; preferably from about 20 to 40 milligrams of ketoprofen compound and from about 200 to 245 milligrams of acetaminophen.

The outstanding properties are most effectively utilized by use of the novel pharmaceutical compositions of the present invention. To prepare the pharmaceutical compositions of this invention, a m-benzoylhydratropic acid compound as primary agent and acetaminophen as a potentiating agent, are intimately admixed with a pharmaceutically acceptable carrier suitable for oral administration. In preparing the compositions in oral dosage form, any of the usual pharmaceutical media may be employed, including liquid carriers such as water, glycols, oils, alcohols and the like for oral liquid preparations such as suspensions, elixirs and solutions; and solid carriers such as starches, sugars, kaolin, calcium stearate, ethyl cellulose, etc. including materials which function as lubricants, binders, disintegrating agents and the like for powders, capsules and tablets. Because of their ease in administration, tablets and capsules represent the most advantageous oral dosage form, these compositions employ solid pharmaceutical carriers such as the aforementioned starches, sugars, kaolin and the like, generally with a lubricant such as calcium stearate. It is especially advantageous to formulate the aforementioned pharmaceutical compositions in dosage unit form for ease of administration and uniformity of dosage. The term "dosage unit form" as used in the specification and claims herein refers to physically discrete units suitable as unitary dosages, each unit containing a predetermined quantity of active ingredient calculated to produce the desired therapeutic effect in association with the required pharmaceutical carrier. Examples of such dosage unit forms are tablets, capsules, pills, powder packets, wafers, teaspoonfuls, tablespoonfuls and the like, and segregated multiples thereof. A dosage unit generally will contain from about 12 to 50 mg of m-benzoylhydratropic acid compound (ketoprofen compound) as primary active ingredient together with from about 170 to 450 mg of acetaminophen. The preferred dosage unit is from about 20 to 40 mg of a m-benzoylhydratropic acid compound together with from about 200 to 425 mg of acetaminophen.

The following examples are given to illustrate the novel compositions and are not to be construed as limiting the invention in spirit or in scope.

EXAMPLE I

1000 hard gelatin capsules, each containing 30 milligrams of m-benzoylhydratropic acid (ketoprofen) as primary active ingredient and 350 milligrams of acetaminophen as potentiating agent are prepared from the following formulation:

    ______________________________________                                                          Grams                                                         ______________________________________                                         Ketoprofen         30                                                          Acetaminophen      350                                                         Starch             250                                                         Lactose            750                                                         Talc               250                                                         Calcium stearate   10                                                          ______________________________________                                    

A uniform mixture of the ingredients is prepared by blending, and used to fill two-piece hard gelatin capsules. The capsules are suitable to be used for providing satisfactory analgesic effect upon administration to subjects suffering from pain.

EXAMPLE II

1000 compressed tablets, each containing as the primary active ingredient 20 milligrams of ketoprofen and 425 milligrams of acetaminophen as potentiating agent are prepared from the following formulation:

    ______________________________________                                                             Grams                                                      ______________________________________                                         Ketoprofen            20                                                       Acetaminophen         425                                                      Starch                750                                                      Dibasic calcium phosphate hydrous                                                                    5000                                                     Calcium stearate      2.5                                                      ______________________________________                                    

The finely powdered ingredients are mixed well and granulated with 10 percent starch paste. The granulation is dried and compressed into tablets. 

What is claimed is:
 1. A pharmaceutical composition suitable for reducing pain in dosage unit form comprising an effective antinociceptive amount in combination of(1) as primary antinociceptive agent, from about 12 to 50 milligrams of a m-benzoylhydratropic acid compound selected from the group consisting of (a) m-benzoylhydratropic acid having the formula ##STR2## and (b) the non-toxic therapeutically acceptable salts thereof, and (2) as potentiating agent, from about 170 to 450 milligrams of acetaminophen; wherein said primary and said potentiating agent are in admixture with a pharmaceutically acceptable carrier.
 2. A composition according to claim 1 in which the primary active agent is m-benzoylhydratropic acid.
 3. A composition according to claim 1 in which the dosage unit form is a tablet.
 4. A composition according to claim 1 in which the dosage unit form is a capsule.
 5. A method for producing analgesia which comprises orally administering to a subject suffering from pain(1) as primary active agent from about 0.2 to 0.83 mg/kg of body weight of a m-benzoylhydratropic acid compound selected from the group consisting of (a) m-benzoylhydratropic acid having the formula ##STR3## and (b) the non-toxic therapeutically acceptable salts thereof, and (2) as potentiating agent from about 2.8 to 7.5 mg/kg body weight of acetaminophen.
 6. A method according to claim 5 in which the primary active agent is employed in an amount from about 0.33 to 0.67 mg/kg of body weight and acetaminophen is employed in an amount of from 3.3 to 7.1 mg/kg of body weight.
 7. A method for producing analgesia which comprises orally administering to a subject suffering from pain(1) as primary active agent from about 12 to 50 milligrams of a m-benzoylhydratropic acid compound selected from the group consisting of (a) m-benzoylhydratropic acid having the formula ##STR4## and (b) the non-toxic therapeutically acceptable salts thereof, and (2) as potentiating agent from about 170 to 450 milligrams of acetaminophen.
 8. A method according to claim 7 wherein the m-benzoylhydratropic acid is employed in an amount of from about 20 to 40 milligrams and acetaminophen is employed in an amount of from about 200 to 425 milligrams. 